This proposal investigates how signals received by and generated within neurons control the developmental program of a neurotrophic virus, herpes simplex virus - 1 (HSV-1). After establishing a permanent, latent infection within peripheral neurons, HSV-1 periodically reactivates to a lytic, replicative state in response to physical or metabolic stress. Significantly, the mechanism(s) by which latent viral genomes located within neuronal nuclei are able to detect reactivating stresses and how immune defenses acting on neurons can counter these reactivating triggers on a molecular level are incompletely understood. Animal and explant models suggest that type I and type II interferons (IFNs), critical effector cytokines that are key components of the multifaceted host innate immune response, are able to prevent stress-induced HSV-1 reactivation. My preliminary data suggests that IFN can function in a neuron- autonomous manner to promote and maintain latency. This proposal focuses on precisely how host neurons control HSV-1 latency in response to IFN treatment. Utilizing a primary, purified neuronal culture model of HSV-1 latency, I propose to define the conditions under which IFN can block stress-induced reaction, the mechanism(s) by which IFN exerts its effects, and whether IFN can promote latency at the time of infection. By determining how exposure of neurons to IFN effects HSV-1 latency and reactivation, I aim to reveal potential targets for clinical interventions to prevent viral reactivtion and to better define neuron-autonomous immune responses to a variety of cellular stresses, including neurotrophic virus infection.